(−)-R-Homocitric acid is an intermediate of biosynthesis of lysine in yeast and in some fungi. (−)-R-Homocitric acid is synthesized in these organisms in enzymatic condensation of α-ketoglutarate and acetylSCoA (Strassman, M.; Ceci, L. N. Biochem. Biophys. Res. Commun., 1964, 14, 262. Strassman, M.; Ceci, L. N. J. Biol. Chem, 1965, 240, 4357. Hogg, R. W.; Broquist, H. P. J. Biol. Chem, 1968, 243, 1839). That pathway is absent in plants and mammalians. Because of that reason is (−)-R-homocitric acid a promising candidate for anti-fungi therapy in mammalians. Homocitric acid is also an important component of the FeMo-cofactor in nitrogenase, which is fixating air nitrogen (Georgiadis, M. M.; Komiya, H.; Chakrabarti, P.; Woo, D.; Kornuc, J. J.; Rees, D. Science 1992, 257, 1653. Kim, J.; Rees, D. C. Science 1992, 257, 1677. Einsle, O.; Tezcan, F. A.; Andrade, S. L. A.; Schmid, B.; Yoshida, M.; Howard, J. B; Rees, D. C. Science 2002, 297, 1696).
Racemic homocitric acid has been synthesized from hydrolysis of diethyl-α-ketoadipate cyanohydrin (Maragoudakis, M., Strassman, M. J. Biol. Chem., 1966, 241, 695) and also starting from ethyl tert-butyl malonate in a three step procedure in 54% yield (Li, Z.-C.; Xu, J.-Q. Molecules, 1998, 3, 31).
The enantiomers of homocitric acid have been obtained by resolution of racemates that were obtained from the chemical synthesis. Thus, the R-enantiomer of homocitric acid γ-lactone has been also obtained by resolution of enantiomers from chemical synthesis in 10% overall yield (Ancliff, R. A., Rusell, T. A., J. Sanderson, A. J. Tetrahedron: Asymmetry, 1997, 8, 3379).
The enantiomers of homocitric acid were obtained by chemical synthesis starting from optically active natural compounds. Thus, S-homocitric acid was first obtained by means of chemical synthesis from (−)-quinic acid as an analytical sample (Thomas, U., Kalaynpur, M. G., Stevens, C. M. Biochemistry, 1966, 5, 2513). Also, S- and R-enantiomers of homocitric acid γ-lactones have been chemically synthesized starting from natural enantiomeric L-lactic acid and L-serine in a multistep procedure in low overall yield (Rodriguez, G. H., Bielmann J.-F. J. Org. Chem. 1996, 61, 1822).
The R-enantiomer of homocitric acid sodium salt was preparatively synthesized from D-malic acid Na-salt in 12% yield using a multiple step procedure (Ma, G.; Palmer, D. R. J. Tetrahedron Lett. 2000, 41, 9209). An improved synthesis of R-homocitric acid and S-homocitric acid from natural D- and L-malic acid correspondingly in a three step procedure in 32-33% overall yield was accomplished (Xu, P.-F.; Matsumoto, Y.; Ohki, Y.; Tatsumi, K. Tetrahedron Letters, 2005, 46, 3815. Xu, P.-F.; Tatsumi, K. Japan Patent Application, 2005, JP2005-075734).
An asymmetric synthesis procedure for R-homocitric acid and S-homocitric acid lactones starting from an achiral 3-hydroxyethyl cyclopentane-1,2-dione is described (Paju, A.; Kanger, T.; Pehk, T.; Eek, M.; Lopp, M. Tetrahedron, 2004, 60, 9081. Lopp, M.; Paju, A.; Pehk, T.; Eek, M.; Kanger, T. Estonian Patent Application EE200400009, decision to grant the patent issued). According to that procedure 3-hydroxyethyl cyclopentane-1,2-dione is transformed to the target compound using two subsequent oxidations (Scheme 1). Depending on the asymmetric oxidation catalyst both enantiomers of homocitric acid lactone—R-homocitric acid γ-lactone or S-homocitric acid lactone can be obtained. In the Scheme 1 the reaction sequence for the synthesis of R-homocitric acid lactone is presented.
From the first oxidation an optically active intermediate X (3-(3-hydroxy-2-oxotetrahydrofuran-3-yl)-propanoic acid R- or S-isomer is obtained in 75% yield. The method describes two options A and B. According to option A intermediate X is oxidized to the target compound II in 50 to 71% yield with KMnO4 or with K2S2O8 in the presence of RuO4. According to option B intermediate X is transformed to 1,7-dioxaspiro[4.4]nonaan-2,6-diooniks (intermediate Y), which is subsequently oxidized to the target compound II. Both options require two different oxidation processes: asymmetric oxidation of 3-hydroxyethylcyclopentan-1,2-dione P-1 and then oxidation of the primary hydroxyl group which is in the scheme bound to the lactone moiety in the compounds X or Y. The described option B requires additionally the transformation of intermediate X to intermediate Y. These reasons make the described method for the synthesis of homocitric acid lactones inefficient.